Introduction

Uses for Flumadine

Treatment of Seasonal Influenza A Virus Infections

Has been used for treatment of influenza caused by susceptible influenza A viruses in adults ≥17 years of age.123511131516333761

Amantadine and rimantadine have little or no activity against influenza B; not used for treatment of influenza B infection.1111315163542

Beginning in the 2005–2006 influenza season, most influenza A (H3N2) strains circulating in the US were resistant to adamantanes (amantadine, rimantadine),121 and resistance to the drugs among seasonal influenza A (H3N2) isolates has remained high during subsequent influenza seasons.105112117144162551552 In addition, the influenza A (H1N1)pdm09 virus circulating during recent influenza seasons is resistant to amantadine and rimantadine.52105112117144151162551552

CDC and other experts recommend that adamantanes (amantadine, rimantadine) not be used for treatment of seasonal influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.112144488

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for treatment of seasonal influenza.112137144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve.144

CDC issues recommendations concerning use of antivirals for treatment of influenza, and these recommendations are updated as needed during each influenza season.137144 Information regarding influenza surveillance and updated recommendations for treatment of seasonal influenza are available from CDC at [Web].

Prevention of Seasonal Influenza A Virus Infections

Has been used for prophylaxis of influenza infection caused by susceptible influenza A viruses in adults, adolescents, and children ≥1 year of age.13478131647

Amantadine and rimantadine have little or no activity against influenza B; not used for prevention of influenza B infection.1111315163542

Annual vaccination with seasonal influenza virus vaccine, as recommended by the US Public Health Service Advisory Committee on Immunization Practices (ACIP), is the primary means of preventing seasonal influenza and its severe complications.113100112116144488 Prophylaxis with an appropriate antiviral active against circulating influenza strains is considered an adjunct to vaccination for control and prevention of influenza in certain individuals.113105112116144488

CDC and other experts recommend that adamantanes (amantadine, rimantadine) not be used for prevention of influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.112144488

Consider viral surveillance data available from local and state health departments and the CDC when selecting an antiviral for prophylaxis of influenza.112137144 Strains of circulating influenza viruses and the antiviral susceptibility of these strains constantly evolve.137144

CDC issues recommendations concerning use of antivirals for prophylaxis of influenza, and these recommendations are updated as needed during each influenza season.137144 Information regarding influenza surveillance and updated recommendations for prevention of seasonal influenza are available from CDC at [Web].

Avian Influenza A Virus Infections

Has been recommended as alternative for treatment or prophylaxis of avian influenza A virus infections† in certain situations.94

CDC and WHO recommend use of a neuraminidase inhibitor (oseltamivir, zanamivir) for treatment or prophylaxis of avian influenza A infections.5094104

If neuraminidase inhibitors unavailable, use of amantadine or rimantadine might be considered an alternative if local surveillance data indicate the strain is known or likely to be susceptible.94 Avian influenza A (H5N1) and avian influenza A (H7N9) generally have been resistant to adamantanes.5094104

Flumadine Dosage and Administration

Administration

Oral Administration

If necessary for use only during emergency situations for patients who cannot swallow tablets or when lower dosage needed, oral suspensions containing 10 mg/mL can be prepared extemporaneously using 100-mg tablets.113 Consult manufacturer's information for specific directions on how to prepare extemporaneous oral suspensions.113

Dosage

Available as rimantadine hydrochloride; dosage expressed in terms of rimantadine hydrochloride.113

Pediatric Patients

Treatment of Seasonal Influenza A Virus Infections

Oral

Children ≥13 years of age†: AAP recommends 100 mg twice daily.105 Manufacturers state not indicated for treatment of influenza in pediatric patients ≤16 years of age.113

Initiate treatment as soon as possible, preferably within 48 hours after onset of symptoms.113

Geriatric Patients

≥65 years of age (including those residing in nursing homes): 100 mg daily for treatment or prevention of influenza A virus infection.113 For treatment in those residing in the community, some clinicians suggest 100 mg twice daily can be considered; reduce dosage to 100 mg daily if adverse effects occur.144 (See Geriatric Use under Cautions.)

Cautions for Flumadine

Contraindications

Known hypersensitivity to adamantane derivatives (rimantadine, amantadine) or any ingredient in the formulation.113

Warnings/Precautions

CNS Effects

Seizure-like activity reported in a few patients with history of seizures who were not receiving anticonvulsants.113

Effect of rimantadine on incidence of seizures in individuals with seizure disorders not fully evaluated.144 Increased incidence of seizures reported when amantadine used in patients with history of epilepsy.113

Resistance

Seasonal influenza A (H3N2) and influenza A (H1N1)pdm09 viruses circulating during recent influenza seasons have been resistant to adamantanes (amantadine, rimantadine).105112144488551552

CDC and other experts recommend that adamantanes (amantadine, rimantadine) not be used for treatment or prevention of influenza in the US until susceptibility to these antiviral agents has been reestablished in circulating influenza A viruses.112144488

Differential Diagnosis

Serious bacterial infections may begin with influenza-like symptoms or may coexist with or occur as complications of influenza.113 No evidence that rimantadine prevents such complications.113

Influenza Vaccination

Although antivirals used for treatment or prevention of influenza, including rimantadine, may be used concomitantly with or at any time before or after influenza virus vaccine inactivated,100 these antivirals may inhibit the vaccine virus contained in influenza vaccine live intranasal.113100 (See Influenza Virus Vaccines under Interactions.)

Specific Populations

Pregnancy

Lactation

Distributed into milk in rats; adverse effects noted in offspring of rats given the drug during the nursing period.113

Pediatric Use

Safety and efficacy for treatment of influenza A virus infection not established in children ≤16 years of age.113 Has been used for the treatment of influenza A infection in children 1–15 years of age†; safety and efficacy appears similar to that in adults.375961

Safety and efficacy for prophylaxis of influenza A virus infection not established in children <1 year of age.113

Geriatric Use

Because geriatric patients may have decreased renal function and may be at increased risk of rimantadine-induced toxicity, reduced dosage usually recommended, especially for elderly nursing home patients.113144 (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution and monitor for adverse effects.113 Use reduced dosage in those with severe hepatic impairment.113 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Use with caution and monitor for adverse effects.113 Use reduced dosage in those with severe renal impairment (Clcr 5–29 mL/minute) or renal failure (Clcr ≤10 mL/minute).113 (See Renal Impairment under Dosage and Administration.)

Interactions for Flumadine

Specific Drugs

No clinically important effect on rimantadine concentrations or AUC113

Influenza virus vaccines

Influenza virus vaccine inactivated: Rimantadine does not interfere with the antibody response to the vaccine113

Influenza vaccine live intranasal: Potential interference with antibody response to the live vaccine; no specific studies113100

Influenza virus vaccine inactivated: May be administered concomitantly with or at any time before or after rimantadine113100

Influenza vaccine live intranasal: Do not administer the live vaccine until ≥48 hours after rimantadine is discontinued; do not administer rimantadine until ≥2 weeks after administration of the vaccine, unless medically indicated;113100 if rimantadine given within 2 weeks after the vaccine, repeat vaccine dose ≥48 hours after last antiviral dose;100 alternatively, if rimantadine given 2 days before to 14 days after the vaccine, revaccinate using the parenteral inactivated vaccine or parenteral recombinant vaccine100

Flumadine Pharmacokinetics

Absorption

Bioavailability

Well absorbed from GI tract; peak plasma concentrations usually attained within 6 hours.11314404951

Special Populations

Healthy geriatric adults 71–79 years of age: Steady-state peak plasma concentrations and AUC are 20–30% higher than in adults 50–70 years of age.113

Geriatric nursing home patients 68–102 years of age: Steady-state concentrations are up to fourfold higher than in healthy young and elderly adults.113

Beginning in the 2005–2006 influenza season, most influenza A (H3N2) strains circulating in the US were resistant to amantadine and rimantadine.121 Resistance to amantadine and rimantadine among seasonal influenza A (H3N2) circulating during recent influenza seasons has remained high.93105112117144162551552

Although amantadine and rimantadine were active against most seasonal influenza A (H1N1) viruses circulating in the US during the 2008–2009 and 2009–2010 influenza seasons,117139162 the influenza A (H1N1)pdm09 virus circulating during recent influenza seasons is resistant to amantadine and rimantadine.52105117144151162551552

Although some strains of avian influenza A (H5N1) have been susceptible to rimantadine,3839 most avian influenza A virus strains tested (including H5N1 and H7N9) are resistant to adamantanes (amantadine, rimantadine).7650104

Inhibits viral replication by interfering with the influenza A virus M2 protein, an integral membrane protein.111131516414246

Strains of influenza A virus with reduced susceptibility to rimantadine have been produced in vitro and have emerged during therapy with the drug.16891011121341424346

Rimantadine-resistant influenza A viruses also are resistant to amantadine and vice versa.91013164142434648

Advice to Patients

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal products, as well as any concomitant illnesses.113

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.113

Importance of advising patients of other important precautionary information.113 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

52. World Health Organization. WHO guidelines for pharmacological management of pandemic influenza A (H1N1) 2009 and other influenza viruses. Revised February 2010. Part I. Recommendations. From WHO website. Accessed 3 Oct 2010. http://www.who.int/csr/resources/publications/swineflu/h1n1_guidelines_pharmaceutical_mngt.pdf

488. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. 12th ed. Washington DC: Public Health Foundation; 2012 May. Updates may be available at CDC website. http://www.cdc.gov/vaccines/pubs/pinkbook/flu.html